Studies have discovered that different extracts of Evodia rutaecarpa and its phytochemicals show a variety of biological activities associated with inflammation. Although rutaecarpine, an alkaloid isolated from the unripe fruit of E. rutaecarpa, has been exposed to have anti-inflammatory properties, the mechanism of action has not been well studied. Thus, this study investigated the molecular mechanisms of rutaecarpine (RUT) in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. RUT reserved the production of nitric oxide (NO) and the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-α), and interleukin (IL)-1β in the LPS-induced macrophages. RUT showed an inhibitory effect on the mitogen-activated protein kinases (MAPKs), and it also inhibited nuclear transcription factor kappa-B (NF-κB) by hindering IκBα and NF-κB p65 phosphorylation and p65 nuclear translocation. The phospho-PI3K and Akt was concentration-dependently suppressed by RUT. However, RUT not only suggestively reduced the migratory ability of macrophages and their numbers induced by LPS but also inhibited the phospho-Src, and FAK. Taken together, these results indicate that RUT participates a vital role in the inhibition of LPS-induced inflammatory processes in RAW 264.7 macrophages and that the mechanisms involve PI3K/Akt and MAPK-mediated downregulation of NF-κB signaling pathways. Notably, reducing the migration and number of cells induced by LPS via inhibiting of Src/FAK pathway was also included to the anti-inflammatory mechanism of RUT. Therefore, RUT may have potential benefits as a therapeutic agent against chronic inflammatory diseases.

The role of activated platelets in acute and chronic cardiovascular diseases (CVDs) is well established. Therefore, antiplatelet drugs significantly reduce the risk of severe CVDs. Evodia rutaecarpa (Wu-Chu-Yu) is a well-known Chinese medicine, and rutaecarpine (Rut) is a main bioactive component with substantial beneficial properties including vasodilation. To address a research gap, we investigated the inhibitory mechanisms of Rut in washed human platelets and experimental mice. At low concentrations (1–5 μM), Rut strongly inhibited collagen-induced platelet aggregation, whereas it exerted only a slight or no effect on platelets stimulated with other agonists (e.g., thrombin). Rut markedly inhibited P-selectin expression; adenosine triphosphate release; [Ca²⁺]i mobilization; hydroxyl radical formation; and phospholipase C (PLC)γ2/protein kinase C (PKC), mitogen-activated protein kinase, and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation stimulated by collagen. SQ22536 (an adenylate cyclase inhibitor) or ODQ (a guanylate cyclase inhibitor) did not reverse Rut-mediated antiplatelet aggregation. Rut was not directly responding to vasodilator-stimulated phosphoprotein phosphorylation. Rut significantly increased the occlusion time of fluorescence irradiated thrombotic platelet plug formation. The findings demonstrated that Rut exerts a strong effect against platelet activation through the PLCγ2/PKC and PI3K/Akt/GSK3β pathways. Thus, Rut can be a potential therapeutic agent for thromboembolic disorders.

Background: Percutaneous coronary intervention (PCI) has been widely used to treat acute coronary syndrome but is only recommended as an additional treatment to medical therapy and risk modification in patients with refractory or progressing angina. The number of PCI in this patient population is still increasing. Post-PCI chest pain (PPCP) is one of the common problems of PCI. Its presentation and causes in patients with stable angina are poorly understood. Patients and methods: This study retrospectively collected clinical information of 167 patients who had stable angina and underwent elective PCI, including 70 patients with PPCP 24 hours after procedure and 97 patients without PPCP. The incidence and predictors of PPCP were analyzed. Results: The incidence of PPCP was 41.9% (70/167). Compared with non-PPCP patients, PPCP patients had more abnormal post-PCI electrocardiogram (ECG) changes (new Q-waves, ST-segment shifts, or T-waves inversion) and serum cardiac troponin I (cTnI) elevation, more PCI vessels, and stent placement (all P<0.05). More PPCP patients required repeat revascularization than non-PPCP patients after PCI (P=0.043). PPCP was correlated with abnormal post-PCI ECG changes (P<0.0001), cTnI elevation (P<0.0001), post-PCI serum level of cTnI (P<0.0001), number of stents placed (P=0.009), and pre-PCI cTnI level (P=0.049). The strongest predictors of PPCP were abnormal post-PCI ECG changes (P<0.0001), post-PCI cTnI level (P<0.0001), and cTnI elevation (P<0.0001), followed by the number of stents placed (P=0.048). Conclusion: PPCP is common in patients with stable angina in our cohort. It is associated with abnormal ECG changes, cTnI elevation, and number of stents placed.

Inflammation is the primary biological reaction to induce severe infection or injury in the immune system. Control of different inflammatory cytokines, such as nitric oxide (NO), interleukins (IL), tumor necrosis factor alpha-(TNF-α), noncytokine mediator, prostaglandin E2 (PGE2), mitogen activated protein kinases (MAPKs) and nuclear factor kappa B (NF-κB), facilitates anti-inflammatory effect of different substances. Coordination metal complexes have been applied as metallo-drugs. Several metal complexes have found to possess potent biological activities, especially anticancer, cardioprotective, chondroprotective and anti-parasitosis activities. Among the metallo drugs, ruthenium-based (Ru) complexes have paid much attention in clinical applications. Despite the kinetic nature of Ru complexes is similar to platinum in terms of cell division events, their toxic effect is lower than that of cisplatin. This paper reviews the anti-inflammatory effect of novel synthetic Ru complexes with potential molecular mechanisms that are actively involved.

Background: Platelets play a crucial role in cardiovascular diseases (CVDs) and are activated by endogenous agonists like collagen. These agonists initiate signal transduction through specific platelet receptors, resulting in platelet aggregation. Glabridin, a prenylated isoflavonoid found in licorice root, is known for its significance in metabolic abnormalities. Glabridin has been observed to inhibit collagen-induced platelet aggregation, but the precise mechanisms, specifically concerning NF-κB activation and integrin α_IIbβ₃ signaling, are not yet fully understood. Methods: In this study, platelet suspensions were prepared from healthy human blood donors, and the aggregation ability was observed using a lumi-aggregometer. The inhibitory mechanisms of glabridin in human platelets were evaluated through immunoblotting and confocal microscopy. The anti-thrombotic effects of glabridin were assessed by histological analysis of lung sections in acute pulmonary thromboembolism and by examining fluorescein-induced platelet plug formation in mesenteric microvessels in mice. Results: Glabridin inhibited integrin α_IIbβ₃ inside-out signals such as Lyn, Fyn, Syk, and integrin β₃ activation and NF-κB-mediated signal events, with similar potency to classical inhibitors BAY11-7082 and Ro106-9920. Glabridin and BAY11-7082 inhibited IKK, IκBα, and p65 phosphorylation and reversed IκBα degradation, while Ro106-9920 only reduced p65 phosphorylation and reversed IκBα degradation. BAY11-7082 reduced Lyn, Fyn, Syk, integrin β₃, phospholipase Cγ2 and protein kinase C activation. Glabridin reduced platelet plug formation in mesenteric microvessels and occluded vessels in thromboembolic lungs of mice. Conclusion: Our study revealed a new pathway for activating integrin α_IIbβ₃ inside-out signals and NF-κB, which contributes to the antiplatelet aggregation effect of glabridin. Glabridin could be a valuable prophylactic or clinical treatment option for CVDs.

Metformin is widely used as first-line medication for type 2 diabetes (T2D), the main disease comorbid with kidney disease, cardiovascular diseases (CVDs), and retinopathy. Platelets are crucial in platelet-dependent arterial thrombosis, which causes CVDs and cerebrovascular diseases. Research indicates that metformin may improve these diseases; metformin reportedly reduced platelet activation in rats. However, no reports have included human platelets. We investigated the mechanisms underlying metformin’s effects on platelet activation by using human platelets and evaluated its in vivo effectiveness in experimental mice. Metformin inhibited platelet aggregation stimulated by collagen but not by arachidonic acid, U46619, or thrombin. Metformin suppressed ATP release, [Ca²⁺]i mobilization, and P-selectin expression, as well as phospholipase C (PLC)γ2/protein kinase C (PKC), p38 mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase (PI3K)/Akt/glycogen synthase kinase-3β (GSK3β) phosphorylation. Metformin did not affect vasodilator-stimulated phosphoprotein (VASP) phosphorylation. In the animal studies, metformin reduced acute pulmonary thromboembolism mortality without increasing bleeding times. These results provide insights into the role and mechanisms of metformin in human platelet activation. Metformin decreased platelet activation by interfering with the PLCγ2/PKC, PI3K/Akt/GSK3β, and p38 MAPK pathways through a VASP-independent mechanism. Metformin demonstrates promise as a new class of antiplatelet agent that can inhibit platelet activation.